4323 ring rheadans from appropriate phthalideisoquinoline a1kaloids. Acknowledgment. We are indebted to our Physical Chemistry Department, under the direction of Dr. R. P. W. Scott, for the spectral and analytical data. We are grateful to Mr. J. Borgese and Mrs. J. Cheung for technical assistance and to Professor G. Buchi, Massachusetts Institute of Technology, for fruitful discussions. (8) Visiting Professor, Institute of Organic and Pharmaceutical Chemistry, University of Innsbruck, Austria.
HNBz
I
I
RocYY 0
x0
la, R = H
b, R = S02Me
W. Kliitzer,* S. Teitel, J. F. Blount, A. Brossi* Chemical Research Department, Hoffmatitt-La Roche Inc. Nutley, New Jersey 07110 Receioed May 29, 1971
(1) (a) E. J. Backus, H, D. Tresner, and T. H. Campbell, Antibiot. Chemorher., 7 , 532 (1957); (b) S . 0. Thomas, V. L. Singleton, J . A. Lowery, R. N. Sharpe, M. Pruess, J. N. Porter, J. H. Mowat, and N. Bohonos, Antibior. Ann., 716 (1956-1957). (2) G. 0. Morton, J. E. Lancaster, G. E. VanLear, W. Fulmor, and W. E . Meyer, J . Amer. Chem. Soc., 91, 1535 (1969). (3) S . Chladek and J. Smrt, Collect. Czech. Chem. Commun., 29, 214 (1964). (4) All new compounds gave satisfactory elemental analyses and nmr spectra. ( 5 ) Addition of iodine monofluoride to glycals is known to lead to glycosyl fluorides: see, e.g., L. D. Hall and J. F. Manville, Chem. Commun., 35 (1968). (6) Satisfactory addition of iodine fluoride t o 2 was also achieved, but in this case separation of the isomeric products was difficult.
2
NBz
Synthesis of the Nucleoside Antibiotic Nucleocidin Sir: Nucleocidin, a fairly broad spectrum antibacterial and antitrypanosomal agent elaborated by Streptomyces caluus, has been shown to have the structure 4'fluoro-5'-O-sulfamoyladenosine (8) although the Dribo configuration has never been unequivocally proved.2 This structure is of particular interest since nucleocidin is the first naturally occurring derivative of a fluoro sugar. We now wish to report a synthesis of this compound which also confirms the proposed structure. Reaction of N~-benzoyl-2',3'-O-isopropylideneadenosine (la), with methanesulfonyl chloride gave the 5'-O-mesyl derivative l b which was not purified but rather directly treated with potassium tert-butoxide in tetrahydrofuran t o give 6-benzamido-9-(5-deoxy2,3-O-isopropylidene-p-D- erythro-pent-4-enofuranosy1)purine (2)4 in a yield of 60% from l a : mp 151-153" (benzene); At::" 230 (E 13,700), 279 nm (e 21,400); nmr (CDCI,) 4.53 (d, 1, Jgem = 2.5 Hz, CY,H), 4.67 (9, 1, Jgem = 2.5 HZ, J 3 ' , 3 / b = 1 HZ, CjfbH), 6.31 (S, 1, CltH), 8.05 and 8.77 ppm (s, 1, C,H and G H ) . Treatment of 2 with benzoyl chloride in pyridine gave the dibenzoyl olefin 3 as a homogeneous foam isolated by chromatography on silicic acid in 90% yield: 249 (E 21,900), 276 nm (E 16,900); nmr (CDCl,) 4.49 (d, 1, J,,, = 2.5 Hz, C;,,H), 4.64 (9, 1, Jgem = 2.5 Hz, J3!,6tb= 1 Hz, G b H ) , 6.33 (s, 1, CIJH), 8.12 and 8.68 ppm (s, I , C2H and CsH). The addition of iodine (4 equiv) to a vigorously stirred solution of 3 (1 equiv) in nitromethane, tetrahydrofuran, or methylene chloride in the presence of freshly ground silver fluoride (5 equiv) led t o a mixture of the epimeric 5'-deoxy-4'-fluoro-5'iodonucleosides 4 and 5 in a combined yield of 809O%.jx6 The ratio of the p-D-ribo (4) and a-L-lyxo (5)
HNBz
C I@ F
3
O
O
x
4a, B = N',N'-Bz,adenine b, B = adenine
N3cw F
O
O
x 6
5a, B = N',N'-Bz,adenine b, B = adenine
NH2 I
7a,R=H b, R = SnBu, c, R = S02NH,
8
isomers varied between 3:2 and 1 :9 depending upon the solvent, temperature, and rate of addition of iodine. Slow addition of solid iodine to a dilute solution of 3 in nitromethane at 0-10" gave good results. Separation of 4 and 5 was achieved by chromatography on a column of silicic acid using 2.5 % acetone in chloroform and preparative tlc using 4 % acetone in chloroform. The more polar p-D isomer (4a) was a homogeneous foam: Xk::l''e 249 (e 21,600), 275 nm (E 17,000); O R D (dioxane) positive Cotton effect with +9700", [%]21so0; [@I23jt' -9800"; nmr CDC1, 5.41 (9, I,J2t,3t =7 Hz, J 3 / p = 12 Hz, C,tH), 6.35 (br s, 1, J1t,4~ 'v 1 Hz, C1jH), 8.15 and 8.67 ppm (s, I , C2H and CsH). The less polar a-L-lyxo isomer 5a was also a foam: 249 (e 22,500), 275 nm (E 17,900); nmr (CDC13) 5.08 (t, I , J 2 ' , 3 ! = J 3 / , F = 5.5 Hz, C ~ J H )6.48 , (9, 1, J1!,2! = 0.5 Hz, J ~ J , F= 2.5 Hz, ClJH), 8.24 (br S, WI/, = 2 Hz, G H ) , 8.70 ppm (s, 1, C2H). It is t o be noted that the D-ribo isomer 4a shows a larger C3),= coupling (trans) than does Sa and that 5a (but not 4a) shows long-range coupling of the 4'-fluorine t o both C1tH and one of the adenine ring protons (probably CsH).' Confirmation of the structure of 4a came from (7) The nmr spectra of these compounds will be considered in detail in a later paper.
Communications to the Editor
4324 debenzoylation of 4a and Sa with methanolic ammp >190" dec: picrate nip 145-147" (1it.I nip 143monium hydroxide followed by heating the resulting 144"); A ~ 259 ~ ~n n i ~ ( E " 15,000): nnir (pyridinenucleosides 4b and 5b in dimethylformamide at 140" d:) 5.03 (d, 2 , J H , I ; = 8.5 Hz, C;,(HZ), 5.25 (9, 1, JIf,?. = for 16 hr. Under these conditions, 4b, like nucleocidin 2 Hz, J2',3' = 6 Hz, CStH), 5.56 (4,1, J?,,3! = 6 Hz, J3',I> itself, formed an ionic N3,5' cyclonucleoside character= 17.5 Hz, C3!H), 6.94 (d, I , J l ! , ? ! = 2 Hz, CIcH), ized by its uv spectrum ,A,(, 274 nm) and its electro8.24 (br s, 2, C6NH2),8.49 and 8.51 ppm (s, 1, C,H and phoretic mobility, while 5b remained unchanged. C8H) as described for nucleocidin.? The antibacterial spectrum of synthetic 8 was very similar t o what has While the iodo function of 4a was readily removed by catalytic hydrogenolysis giving the corresponding 5'been reported for natural nucleocidin. deoxy-4'-fluoronucleoside with, , A, 250 ( E 22,300), 273 The above series of reactions has also been carried out i n the a-L-lyxofuranosyl series starting with 5. nm ( E 16,800); nmr (CDC13) 1.65 (d, 3. J H , F = 17 Hz, These results, together with the preparation of some C,/H,) 6.30 (br s, 1, J1),?t'v 1 Hz, CITH),8.13 and 8.69 analogs of nucleocidin, will be described in full at a (s, 1, C2H and CxH), its nucleophilic displacement later date. proved t o be very difficult. None of the oxygen nucleophiles tried proved satisfactory but reaction of 4a (1 1 ) Syntex Postdoctoral Fellow, 1969-1971. with lithium azide in dimethylformamide at 100" for 20 I. D. Jenkins," J. P. 11. Verheyden, J. C. Moffatt* hr followed by debenzoylation with methanolic amCoiitributioii No. 90 monia gave 5'-azido-5'-deoxy-4'-fluoro-2',3'-0-isolirstifirte of Molc,cular Biology, Syiitex Research propylideneadenosine (6) in 93 yield: 258 Ptrlo Alto, Coliforiritz 94304 nm ( E 13,300);, ,A, (KBr) 4.70 y (N3); ninr (CDCI3) Receiced Julie 17. 1971 3.61 (d, 2, J H , F = 13.5 Hz, CjIHC), 5.58 (9, l,JCl,B' = 6 Hz, J31,F = 12.5 Hz, C,(H), 6.38 (s, 1, C1/H), 7.93 and 8.41 ppm (s, 1, C2H and CsH).' While catalytic reduction 6-Methyl Penicillins and 7-Methyl Cephalosporins of the azido function of 6 and its N'i-benzoyl derivative t o the corresponding 5'-aniino-4'-fluoronucleosides Sir: was readily achieved, subsequent attempted deaniinaIt has been well established',? that penicillins and tion with nitrous acid led t o complex mixtures. cephalosporins inhibit bacterial cell-wall synthesis by Conversion of the azido function of 6 to the desired interfering with the final cross-linking process, which hydroxyl group was achieved by ultraviolet irradiation has been termed transpeptidation and involves an amino of a benzene solution of 6 in a Pyrex apparatus.8 The group i n a peptidoglycan molecule and the D-ahnylresulting intermediate 5'-imine was hydrolyzed t o the D-alanine end of the acetyl -muraniyl pentapeptide 5'-aldehyde by brief acidic treatment and then directly fragment i n another. It has been suggested that the reduced with sodium borohydride giving 4'-fluoro-2', chemical structures of both penicillins and cephalo3'-0-isopropylideneadenosine(7a) with nip 225-226" sporins can mimic this D-alanyl-o-alanine residue and from methanol: '';A:: 258 n n i ( E 13,200); O R D thereby inhibit (irreversibly) the enzyme transpeptidase (MeOH) negative Cotton effect with [@]?2$' - 2000", responsible for the cross-linking. 6-Methyl penicillins 0", and [@]2aoPk +3800"; nnir (pyridine-d,) 4.19 and 7-methyl cephalosporins have been proposed' as (d, 2, J H , F = 9.5 Hz, CA'H?), 5.90 (9, I , Jer,a, = 6 Hz, more analogous t o D-alanyl-o-alanine than their parent J3f,F= 12 Hz, Ca,H), 6.90 (s, I , C1!H), 8.45 and 8.56 molecules, since both classes bear a niethyl group in the ppni (s, I , C,H and CaH). same position a s is found i n the D-alanyl residue. It has The reactions of 7a with sulfamoyl chloride using been suggested that they may, therefore, show enhanced either pyridine or sodium hydride as baseg gave the 5'effectiveness as antibacterial agents. T o examine this sulfamate 7c in low yields. If, however, 7a was first hypothesis, we habe synthesized both a 6-methyl penitreated with an excess of bis(tributy1tin) oxide in recillin and a 7-methyl cephalosporin. fluxing benzene with azeotropic removal of water it was 6-Methyl-6-phenylacetamidopenicillanic acid, methyl converted into the corresponding 5'-0-tributyltin ether ester (V) was prepared by the following sequence of reac(7b). Without isolation this conipound was treated'O with sulfanioyl chloride at 5" for 10 min giving the 5 ' 0-sulfamate 7c i n 8 7 z yield as the hydrate with mp 162-165" from water: X ~ ~ ~ , "259 " nm ( E I5,SOO); nmr (pyridine-&) 4.9 (,ABX multiplet, 2, CjfHZ deI. R = a-H shielded 0.70 ppm relative t o 7a), 5.92 (q, l , J.f,a( = 11. R = a-CH 6 Hz, J3p,F= 12 Hz, C,.H), 6.86 (s, I , CIfH), 8.46 and Ill. R S-CH 8.51 ppm (s, 1, C?H and C8H). Treatment of 7c with 90% trifluoroacetic acid at 23" for 30 min gave 4'- tions. Treatment of N-benzylidene-6-aiilinopenicilfl u or 0-5 '- 0 - s ul fa m oy1a den osi ne (8) as the m on oh yd r a t e lanic acid, methyl ester ( I ) with 1 equiv of sodiunihydride in 60% yield after two recrystallizations from water: and excess methyl iodide in dimethoxyethane at 0" gave a mixture of epimeric 6-methyl derivatives [II, 90% yield; ninr (CDCla) 522 (s, 1 H), 322 (s, 1 H), 108 (s, (8) Photochemical conversions of primary sugar azitlcs to aldehydes have been described: D. Horton, A . E. Luetzow, and J . C. Wease, 3 H) Hz; 111, 5 % yield; nmr (CDCI:,), 516 (s, 1 H), Carbohj d. Res., 8, 366 (1968). 329 (s, 1 H), 268 (s, 1 H) Hz]. Crystallization from (9) These methods have been successfully used for sulfamation of dichloromethane-hexane gave white, solid I 1 (nip 83.2',3'-O-isopropylideneadcnosine: D. A. Shuman, M. J. Robins, and R . I
